1. Chapter 15. Surfactants

2. Contents INTRODUCTION SUBJECTS CONCLUSION Surfactant molecules
Surface and interfacial tension
INTRODUCTION
Behavior of surfactants & Gibbs equation
Insoluble monolayers
Adsorption
Micellisation
Liquid crystals & Vesicles
Solubilisation
SUBJECTS
Summary
CONCLUSION

3. Surfactant molecules Surface & interfacial tension
INTRODUCTION
Surfactant molecules
Surface & interfacial tension

4. Properties of surfactants
Characterized by two distinct regions in structure
Hydrophilic region
Hydrophobic region
Amphipathic molecule
Properties of surfactants
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

5. Classification of Surfactants
Generally classified by Hydrophilic group
Anionic
Cationic
Zwitterionic
Nonionic
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

6. Surface and interfacial tension
Imbalance between attractive forces
[Air or immiscible phase]
[Water]

7. Surface and interfacial tension
Generally between the values of surface tension of involved liquids.
n-Octanol against water
Much lower than pure liquid
Hydrogen bonding between liquids
→ Cohesive force ↑
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

8. Behavior of surfactants Gibbs equation
SUBJECTS
Behavior of surfactants
Gibbs equation

9. Behavior of Surfactants
Tendency to accumulate the boundary between two phases
Escape from a hostile environment
Minimize free energy state
Reduce interfacial tension
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

10. Behavior of Surfactants
Increasing the concentration of surfactants
Surface becomes saturated with surfactant molecules.
Form small spherical aggregates or micelles
Critical Micelle Concentration (CMC)
Calculate the area occupied by a surfactant molecule using the Gibbs equation.
Air
Water
Surface
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

11. Gibbs adsorption equation
Surfactant molecule equilibrium between surface and bulk solution
Γ=− 1 𝑅𝑇 𝑑γ 𝑑 ln 𝑐 =− 𝑐 𝑅𝑇 𝑑γ 𝑑𝑐
γ : surface tension
Γ : the amount of component in the surface (# of moles / m2)
c : concentration of surfactant
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

12. Gibbs adsorption equation
Application of the Gibbs equation
Just below the cmc, surfactant molecules are closely packed in the surface.
The area A that each molecule occupies at the surface
𝐴= 1 𝑁 𝐴 Γ 1m
Γ : the amount of component in the surface (# of moles / m2)
NA: the Avogadro constant
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

13. Surface activity of drugs
Amphipathic nature of the drugs
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

14. SUBJECTS
Insoluble monolayer

15. Insoluble monolayers
Insoluble amphiphilic compounds can form films on water surfaces.
Dissolve the surfactant in a volatile solvent and carefully injecting the solution onto the water.
* J. Phys. Chem. B, 2004, 108,
Yoshikito Moroi, Muhammad Rusdi, and Izumi KUbo

16. Insoluble monolayers Langmuir trough
Apparatus for study of monolayers on a laboratory scale
Measuring
surface pressure
Monolayer
Surface pressure π=γ0-γm
γ0: Surface tension of the clean surface
γm : Surface tension of the film-covered surface
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

17. Insoluble monolayers Three types of monolayer states
Solid or condensed monolayers
Gaseous monolayers
Liquid or expanded monolayers
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

18. Monolayer states Solid or condensed state
Rises abruptly when the molecules become tightly packed.
At high pressures, the molecules are in contact and orientated vertically in the surface.
The extrapolated surface area is very close to the cross-sectional area of molecule.
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

19. Monolayer states Gaseous monolayers
The molecules move around in the film, remaining a sufficiently large distance apart.
Upon compression, there is a gradual change in the surface pressure.
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

20. Monolayer states Expanded monolayers
Intermediate states between condensed and gaseous films
Close packing is prohibited by bulky side-chains, or cis-configuration.
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

21. Monolayer states Transition between monolayer states
As the film is compressed, transition between phases can occur.
Condensed phase
Gaseous phase
Begin to stand upright
Lying along the surface
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

22. Pharmaceutical applications
Study of polymers used as packaging materials and film coatings
To assess the suitability of polymer as potential enteric and film coatings
At pH 3.1, more tightly packed film
 Restrict dissolution in the stomach
At pH 6.5, more expanded film
 Allow penetration and disintegration
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

23. Pharmaceutical applications
Cell membrane models
Useful models for studying drug-lipid interactions
TFP  remains in the monolayer CPZ  excluded from the interface
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

24. Adsorption at the solid/liquid interface Adsorption isotherms
SUBJECTS
Adsorption at the solid/liquid interface
Adsorption isotherms

25. Adsorption at the solid/liquid interface
Adsorption vs. Absorption
Adsorption
The process of accumulation at an interface
Absorption
The penetration of one component throughout the body

26. Adsorption at the solid/liquid interface
Two general types of adsorption
Physical adsorption
Adsorbate is bound to the surface through the weak van der Waals forces
Chemical adsorption (Chemisorption)
Involves the stronger valence forces
Usually involves an ion-exchange process

27. Adsorption at the solid/liquid interface
Adsorption isotherms
Langmuir equation
Monolayer adsorption
Freundlich equation
Multilayer adsorption
Freundlich
Langmuir
The concentration of solute adsorbed onto the solid phase
* Vadose Zone Journal, 2007, 6(3),
Sabine Goldberg, Louise J. Criscenti and Kirk J. Cantrell

28. Adsorption isotherms Langmuir equation 𝑥 𝑚 = 𝑎𝑏𝑐 1+𝑏𝑐
𝑐 𝑥/𝑚 = 1 𝑎𝑏 + 𝑐 𝑎
Linear form
a: related to surface area
b: related to the enthalpy of adsorption
c: concentration of solution
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

29. Adsorption isotherms Increase of concentration Freundlich equation
Deviations from the typical Langmuir plot can occur.
Formation of multi adsorption layers
Freundlich equation

30. Adsorption isotherms Freundlich equation 𝑥 𝑚 =𝑎 𝑐 1/𝑛
a, n: constants
1/n: related to the intensity of drug adsorption
c: concentration of solution
log 𝑥 𝑚 = log 𝑎 +( 1 𝑛 ) log 𝑐
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

31. Factors affecting adsorption
Solubility of adsorbate pH
Nature of adsorbent
Temperature

32. Solubility of the adsorbate
Factors affecting adsorption
Lundelius’s Rule
Adsorption of a solute is inversely proportional to its solubility.
Ex) Adsorption of iodine onto carbon
CCl4:CHCl3:CS2 = 1:2:4.5  Inverse ratios for the solubility
The greater the solubility, the stronger are solute-solvent bonds
Solute-solvent bonds must first be broken for adsorption.
 The smaller the extent of adsorption!

33. pH Adsorption increases as the ionisation of the drug is suppressed.
Factors affecting adsorption
Adsorption increases as the ionisation of the drug is suppressed.
The extent of adsorption reaches a maximum when the drug is completely uninonised.
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

34. Nature of the adsorbent
Factors affecting adsorption
Surface area of the adsorbent
The most important property affecting adsorption
Extent of the adsorption is proportional to the specific surface area.
Adsorbent-adsorbate interactions
Particular adsorbents have affinities for particular adsorbates
Ex) Digoxin - Antacids
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

35. Temperature Adsorption is generally an exothermic process
Factors affecting adsorption
Adsorption is generally an exothermic process
Increase in temp  Decrease in the amount adsorbed
Small variations in temp tend not to alter the adsorption process to a significant extent

36. Pharmaceutical applications
Adsorption of poisons/toxins
Activated charcoal, magnesium oxide, tannic acid
Taste masking
Diazepam
Haemoperfusion
Carbon haemoperfusion
Adsorption in drug formulation
Improved dissolution rate, the stabilisation of suspensions

37. Micellisation & Micellar structures
SUBJECTS
Micellisation & Micellar structures

38. Micellisation Micelles Small aggregates formed after the cmc
Critical Micelle Concentration (CMC)
Concentration over which micelles are formed

39. Micellisation In dynamic equilibrium with free molecules in solution
Association colloids
Driving force for micelle formation
To attain a state of minimum free energy
Remove the hydrophobic group from
the aqueous environment

40. Micellar structure Critical packing parameter (CPP)
Consider the geometry of the surfactant molecule
CPP determines the preferred association structures assumed for each molecular shape.
𝐶𝑃𝑃= 𝑣 𝑙 𝑐 𝑎
v: volume of one chain
a: cross-sectional area of surfactant head group
lc: extended length of the surfactant alkyl chain
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

41. Micellar structure CPP ≤ 1/3 Single hydrophobic chain
Simple ionic or large nonionic head group
 Spherical micelle
Most surfactants of pharmaceutical interest fall into this category.
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

42. Micellar structure 1/3 < CPP ≈ 1 Additional second alkyl chain
 Bilayer (non-spherical structures)
Form vesicles
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

43. Micellar structure 1 < CPP
In nonaqueous media, reverse (or inverted) micelles may form.
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

44. Micellar structure of ionic micelles
Stern layer
For most ionic micelles, the degree of ionisation (α) is between 0.2 ~ 0.3; 70~80 % of the counterions may be bound to the micelles
Gouy-Chapman electrical double layer
Outer surface of the Stern layer
Contain 20~30 % counterions to neutralise the charge on the micelle
Gouy-Chapman layer
Stern layer
* Fast track – Physical Pharmacy
Alexander T Florence and David Attwood

45. Micellar structure of ionic micelles
In highly concentrated solution
The micelles elongating to form cylindrical structures with many ionic systems.
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

46. Micellar structure of ionic micelles
Larger than ionic micelles
Absence of an electrical work for additional monomer into ionic micelle
Frequently asymmetric
Hydrophobic core surrounded by a shell of oxyethylene chains
The palisade layer (highly hydrated)
* Fast track – Physical Pharmacy
Alexander T Florence and David Attwood

47. Factors affecting the CMC and size
Structure of the hydrophobic group
Nature of the hydrophilic group
Type of conterion
Addition of electrolytes
Temperature

48. Structure of the hydrophobic group
Factors affecting CMC and size
Compounds with rigid aromatic or heteroaromatic ring structures
Purines, pyrimidines, etc.
 Face-to-face stacking of molecules one on top of the other
 Do not exhibit cmc
Length of Hydrocarbon chain
Increase length  Increased hydrophobicity  Decreased cmc

49. Structure of the hydrophobic group
Factors affecting CMC and size
Effect of substituents on hydrophobicity can be roughly estimated.
Hydrophobicity
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

50. Nature of the hydrophilic group
Factors affecting CMC and size
Nonionic surfactants
Not involve any electrical work
 Much lower CMC and higher aggregation number
Increase in the ethylene oxide chain length
 Make more hydrophilic and the CMC increases
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

51. Type of counterion Cationic surfactant Anionic surfactant
Factors affecting CMC and size
Cationic surfactant
Cl- < Br- < I-
Anionic surfactant
Na+ < K+ < Cs+
The weakly hydrated ions can be adsorbed more readily in the micellar surface
 Decrease the charge repulsion between the polar groups
Increase in micellar size

52. Addition of electrolytes
Factors affecting CMC and size
Reduction of repulsion forces by electrolytes
 Lower CMC and higher micellar size
Decrease
Increase
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

53. Temperature Cloud point
Factors affecting CMC and size
Cloud point
Temperature over which aqueous solutions of nonionic surfactants become turbid
Reversible process of phase separation
Increase in the micellar aggregation number
Change in micellar interactions
The dehydration process
Mechanism
* J. Chromato. A, 2000, 902,
R. Carabias-Martinez, E. Rodriguez-gonzalo,, and B. Moreno-Cordero

54. Temperature Comparatively small effect on ionic surfactants
Factors affecting CMC and size
Comparatively small effect on ionic surfactants
Ionic surfactant
Nonionic surfactant
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

55. Liquid crystals Vesicles
SUBJECTS
Liquid crystals
Vesicles

56. Liquid crystals Thermotropic liquid crystal Lyotropic liquid crystal
State of matter that have properties between those of a conventional liquid and those of a solid crystal
Thermotropic liquid crystal
Phase transition into liquid crystal phase as temperature is changed.
Lyotropic liquid crystal
Phase transition as a function of both temperature and concentration

57. Thermotropic liquid crystals
Produced when certain substances are heated
Three types of thermotropic liquid crystals
Nematic (soap-like) liquid crystals
Orientate with long axes parallel, but not ordered into layers
Mobile and orientated by electric or magnetic fields
Parallel
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Alexander T Florence and David Attwood

58. Thermotropic liquid crystals
Smectic (thread-like) liquid crystals
Arrange with long axes parallel, also arranged into layers
Viscous and not oriented by magnetic fields
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

59. Thermotropic liquid crystals
Cholesteric (chiral nematic) liquid crystals
Formed by several cholesteryl esters
Stack of very thin two-dimensional nematic-like layers
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

60. Lyotropic liquid crystals
The liquid crystalline phases that occur on increasing the concentration of surfactant solutions
As increase of concentration of surfactant
Spherical micelle  elongated or rod like micelle
 hexagonal phase (middle phase)
 cubic phase (with some surfactants)
 neat phase (lamellar phase)
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

61. Vesicles
Formed by phospholipids and other surfactants having two hydrophobic chains (CPP≈1)
Liposomes
Multilamellar or unilamellar
Used as drug carriers
Disadvantages
Phospholipids  Oxidative degradation
 Nitrogen atmosphere
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

62. Vesicles Surfactant vesicles
Formed by surfactants having two alkyl chains
Sonication  Single-compartment vesicles
Use of vesicles formed by ionic surfactants
 membrane models (due to toxicity)
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

63. Vesicles Surfactant vesicles Niosome
Nonionic surfactants-based vesicles  Less toxic and potential use in DDS
Behave in vivo like liposomes
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

64. SUBJECTS
Solubilisation

65. Solubilisation
Process whereby water-insoluble substances are brought into solution by incorporation into or onto micelles.
Solubilisate
Incorporated substance
Maximum additive concentration (MAC)
Maximum amount of solubilisate that can be incorporated into system
Determining of MAC
By visual inspection
From extinction of turbidity measurement on the solutions

66. Location of the solubilisate
Related to the chemical nature of the solubilisate
Nonpolar solubilisates
 Hydrocarbon core
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

67. Location of the solubilisate
Related to the chemical nature of the solubilisate
Water insoluble compounds containing polar groups
 Polar group at the core-surface
interface
 Hydrophobic group buried inside
the hydrocarbon core
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

68. Location of the solubilisate
Related to the chemical nature of the solubilisate
Water soluble molecules
 In the polyoxyethylene shell
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

69. Factors affecting solubilisation
Nature of the surfactant
Nature of the solubilisate
Temperature

70. Nature of the surfactant
Factors affecting CMC and size
Chain length of hydrophobe
(when solubilisate is located within the core)
Increase in alkyl chain length
 Solubilisation capacity increases
C12
Length
C18
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

71. Nature of the surfactant
Factors affecting CMC and size
Ethylene oxide chain length
Increase in the hydrophilic chain length
 Solubilisation capacity increases
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

72. Nature of the solubilisate
Factors affecting CMC and size
Increase of alkyl chain length  Decrease in solubility
Effect of steroid structure on solubilisation
More hydrophilicity of the substituent in C17 of the ring
Lower quantity of surfactant required
Increase in solubility
-COCH3 < -OH < -COCH2OH
C17
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

73. Temperature Increase of temperature  Increase of solubilisation
Factors affecting CMC and size
Increase of temperature  Increase of solubilisation
Complicating factor when considering the effect of temperature on the amount solubilised is the aqueous solubility of solubilisate.
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

74. Temperature Study of the solubilisation of benzoic acid
Factors affecting CMC and size
Study of the solubilisation of benzoic acid
Increase in aqueous solubility
Increase in solubilisation
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

75. Pharmaceutical applications
Solubilisation of phenolic compounds
Form clear solutions  For use in disinfection
Solubilisation of iodine in nonionic surfactant micelles (iodophors)
Reduction of corrosion problems  For use in instrument sterilisation
Solubilisation of drugs
Steroids, water-insoluble vitamins, etc.

76. CONCLUSION
Summary

77. Summary
Surface and interfacial tensions arise because of an imbalance of attractive forces on the molecules.
Surfactant molecules have hydrophilic and hydrophobic regions and adsorb at interfaces for attaining minimum free energy state.
The extent of adsorption at the interface can be calculated using the Gibbs equation

78. Summary
Insoluble amphiphilic compounds will form films on water surfaces and these may be tightly packed.
Condensed, Expanded, Gaseous film
Adsorption of solutes onto solid surfaces from solution can occur by physical adsorption
Langmuir equation (monolayer), Freundlich equation (multilayer)
Micelles form at the critical micelle concentration.
The main driving force for the formation is the increase entropy when the hydrophobic regions of the surfactant are removed from water.

79. Summary Micellar structure
Ionic micelle  Stern layer, Gouy-Chapman layer
Nonionic micelle  Palisade layer (highly hydrated), Cloud point
Critical Packing Parameter (CPP)  Preferred association structure
An important property of surfactant micelles is their ability to solubilise water-insoluble compounds
The location of solubilisates is related to the chemical nature of molecule.